Thirty-one new gene regions linked with blood pressure have been identified in one of the largest genetic studies of blood pressure to date, involving over 347,000 people, and jointly led by Queen Mary University of London (QMUL) and the University of Cambridge.

The discoveries include DNA changes in three genes that have much larger effects on blood pressure in the population than previously seen, providing new insights into the physiology of hypertension and suggesting new targets for treatment.

High blood pressure or hypertension is a major risk factor for cardiovascular disease and premature death. It is estimated to be responsible for a larger proportion of global disease burden and premature mortality than any other disease risk factor. However, there is limited knowledge on the genetics of blood pressure.

The teams investigated the genotypes of around 347,000 people and their health records to find links between their genetic make-up and cardiovascular health. The participants included healthy individuals and those with diabetes, coronary artery disease and hypertension, from across Europe (including the UK, Denmark, Sweden, Norway, Finland and Estonia), the USA, Pakistan and Bangladesh. The study brought together around 200 investigators from across 15 countries.

Study author Professor Patricia Munroe from QMUL said:

“We already know from earlier studies that high blood pressure is a major risk factor for cardiovascular disease. Finding more genetic regions associated with the condition allows us to map and understand new biological pathways through which the disease develops, and also highlight potential new therapeutic targets. This could even reveal drugs that are already out there but may now potentially be used to treat hypertension.”

Most genetic blood pressure discoveries until now have been of common genetic variants that have small effects on blood pressure. The study, published in Nature Genetics, has found variants in three genes that appear to be rare in the population, but have up to twice the effect on blood pressure.

Study author, Dr Joanna Howson from the University of Cambridge said:

“The sheer scale of our study has enabled us to identify genetic variants carried by less than one in a hundred people that affect blood pressure regulation. While we have known for a long time that blood pressure is a risk factor for coronary heart disease and stroke, our study has shown that there are common genetic risk factors underlying these conditions.”

Queen Mary University of London www.whri.qmul.ac.uk/about-us/whri-news/94-news/627-major-global-study-reveals-new-hypertension-and-blood-pressure-genes

Three-year-old Naomi slaps her forehead a few times, bites her fingers and toddles across the doctor’s office in her white and pink pyjamas before turning her head into a door with a dull thud. Her mother quickly straps on a helmet and adjusts the rainbow chinstrap, then watches as Naomi puts a hand back in her mouth and continues exploring the room.

“She keeps me busy,” acknowledges her mother, Laura Elguea.

Naomi was diagnosed at age 2 with Rett syndrome, a rare, debilitating disease in which patients progressively lose brain function and the ability to walk. While she laughs, smiles and toddles around like most 3-year-olds, Naomi’s repetitive hand behaviours offer clues to her condition.

Relatively little is known about the neuronal causes of Rett syndrome, but UT Southwestern Medical Center scientists have now identified a process in the brains of mice that might explain the repetitive actions – research that could be a key step in developing treatments to eliminate symptoms that drastically impair the quality of life in Rett patients.

The finding from UT Southwestern’s Peter O’Donnell Jr. Brain Institute could also potentially benefit people with autism spectrum disorder, though more research is needed to evaluate the link to this disease in humans.

“We are exploring the processes that contribute to Rett syndrome in an effort to develop treatments that may prove useful in the disease,” said Dr. Lisa Monteggia, Professor of Neuroscience with the O’Donnell Jr. Brain Institute, who led the research.

The study demonstrated that MeCP2 – the protein that does not work properly in Rett syndrome – is among a group of three proteins that affect the function of a gene previously linked to obsessive compulsive disorder. Researchers were able to induce and then suppress repetitive behaviours in mice by changing the levels of these three proteins at the synapse – the communication junction between nerve cells.

The research is a significant advancement in the understanding of how dysfunction in MeCP2 leads to key symptoms associated with Rett syndrome. Although MeCP2 was identified less than two decades ago as the cause of the postnatal neurological disorder, the link between the protein’s dysfunction and the specific neurological symptoms characteristic of the disease remains elusive.

Rett syndrome affects girls almost exclusively, occurring in 1 of every 10,000 to 15,000 births and usually diagnosed by age 2. It is characterized by developmental regression, autistic traits, slow brain development, lack of speech, repetitive hand movements, seizures, and problems with walking. Many patients live beyond middle age, though not enough data exist to reliably estimate life expectancy beyond age 40.

While current medications and behavioural therapy can sometimes diminish symptoms such as seizures and hand behaviours, no treatment exists to eradicate or reverse the disorder and the repetitive stereotyped behaviours, due in large part to a lack of knowledge about how MeCP2 dysfunction gives rise to these and other symptoms.

UT Southwestern Medical Center www.utsouthwestern.edu/newsroom/news-releases/year-2016/september/rett-syndrome-monteggia.html

While searching for  a non-invasive way to detect prostate cancer cells circulating in blood, Duke Cancer Institute researchers have identified some blood markers associated with tumour resistance to two common hormone therapies.

In a study, the Duke-led team reported that they isolated multiple key gene alterations in the circulating prostate tumour cells of patients who had developed resistance to abiraterone or enzalutamide.

Enzalutamide is a drug that blocks the male androgen receptor, and abiraterone is a drug that lowers testosterone levels. Both drugs are approved to treat hormone-resistant prostate cancer, but the tumours typically develop resistance within a few years. 

The study, focusing on a small number of patients and using sophisticated blood analysis technology, demonstrated that circulating tumour cells detected in blood have the potential to reveal important genetic information that could guide treatments selection in the future, and suggest targets for new therapies.

“We have developed a method that allows us to examine the whole genome of rare circulating cancer cells in the blood, which is unique in each patient, and which can change over time during treatment,” said senior author Andrew Armstrong, M.D., a medical oncologist and co-director of Genitourinary Clinical-Translational Research at the Duke Cancer Institute (DCI).

“Among the genomic changes in the patients’ individual cancers, we were able to find key similarities between the cancer cells of men who have hormone-resistant prostate cancer,” Armstrong said. “Our goal is to develop a ‘liquid biopsy’ that would be non-invasive, yet provide information that could guide clinical decisions.”

Armstrong and colleagues from the DCI and the Duke Molecular Physiology Institute used a process called array-based comparative genomic hybridization to analyse the genome of the circulating tumour cells of 16 men with advanced, treatment-resistant prostate cancer. The technique enabled them to determine which genes had extra copies and which regions were deleted.

Focusing both on genes that have previously been implicated in tumour progression, plus other genes important to cancer biology, the researchers found changes in multiple genetic pathways that appear to be in common among the men’s circulating tumour cells.

“Our research provides evidence supporting the ability to measure gains and losses of large scale sections of the circulating tumour cells genome in men with prostate cancer,” said co-author Simon Gregory, Ph.D., director of the Section of Genomics and Epigenetics in the Duke Molecular Physiology Institute. “We are now evaluating this method combined with higher resolution DNA mutational studies and measurements of RNA splice variants in CTCs to determine their clinical relevance to patients and treatment resistance.”

Should these common alterations be similarly identified in larger studies, they could be used as biomarkers as part of a blood-based liquid biopsy to help determine what treatments would be most effective. The findings could also point to new targets for drug development.

One such large prospective clinical validation study is underway now at the Duke Cancer Institute, which is examining how the mutations develop in the context of enzalutamide or abiraterone therapy, and how the mutations relate to other key genetic events.

Duke University corporate.dukehealth.org/news-listing/duke-team-identifies-blood-biomarkers-drug-resistant-cancer-tumor-cells?h=nl

The first patient was a mystery.

Arriving at Duke six years ago at the age of three, the youngster had mild developmental delays and physical characteristics that included a large body and large head circumference. A genetic analysis showed mutation of a specific gene, known as ASXL2, which had never been singled out as causing disease.

The youngster’s doctor, Vandana Shashi, a professor of paediatrics for the Division of Medical Genetics at Duke University School of Medicine, told his parents their son likely had a rare and yet-unidentified disease. And she promised to remain vigilant if any other cases popped up in the medical literature that might provide additional clues.

After none turned up, Shashi set out to see if the mystery case might be solved, instead, using the tools of the Undiagnosed Diseases Network (UDN) at the National Institutes of Health, which links Duke and six other medical teaching sites around the country. The participating centres pool information and innovations about diseases that are so rare they often stump the broader medical community.

Within just six weeks — connected to other UDN research labs and an international database of genes and disease characteristics called GeneMatcher — Shashi had a remarkable trove: Five additional children, all with the same physical features and the ASXL2 gene mutation.

“We can now definitively say this is a newly identified disease,” Shashi said. “With just one case, we could not say the gene mutation was the underlying cause. But with six cases, all with the same ASXL2 mutation, it is definitive.”

The new disease, which still has no name, does have similarities to two other rare genetic disorders arising from related genes. A condition called Bohring-Opitz syndrome is the result of a mutation of the ASXL1 gene, while Bainbridge-Ropers syndrome is caused by a flaw in the ASXL3 gene. Both conditions are also rare, and result in similar, but more severe impairments.

It’s unknown how the ASXL2 genetic mutation arises, but Shashi said identifying the root cause of the children’s condition is a first step, and could help drive new therapies and treatment approaches.

The immediate benefit is to the families of the children, who now have an answer to their most basic question.

“It has been wonderful to be connected to other families who share this genetic condition,” said Teresa Locklear, whose son, Issac, was the first patient to present with the mutation at Duke. “When we started, we hoped we would find other families with children who were older than Isaac, to provide a sort of roadmap for what to expect. But it turns out, Isaac is the oldest and we are the ones sharing our experiences with parents of younger children, and that’s been so rewarding.”

Study co-author Loren del Mar Peña, assistant professor in the Department of Pediatrics at Duke, said reducing isolation for families with a rare disease has tremendous impact.

“These families feel truly alone when their child clearly has a disorder, and yet there is no name for it, and no community of people they can relate to with shared experiences,” Peña said. “This will help them be able to connect with others and compare notes. That’s a huge deal – to know you aren’t the only one and there a five other children out there.”

Duke University corporate.dukehealth.org/news-listing/network-and-gene-tools-help-quickly-identify-new-rare-genetic-disease

Penn State biomaterials scientists have developed a new, inexpensive method for detecting salt concentrations in sweat or other bodily fluids. The fluorescent sensor, derived from citric acid molecules, is highly sensitive and highly selective for chloride, the key diagnostic marker in cystic fibrosis.

‘Salt concentrations can be important for many health-related conditions,’ said Jian Yang, professor of biomedical engineering. ‘Our method uses fluorescent molecules based on citrate, a natural molecule that is essential for bone health.’

Compared to other methods used for chloride detection, Yang’s citrate-based fluorescent material is much more sensitive to chloride and is able to detect it over a far wider range of concentrations. Yang’s material is also sensitive to bromide, another salt that can interfere with the results of traditional clinical laboratory tests. Even trace amounts of bromide can throw off test results. With the citrate-based sensor, Yang’s group can distinguish the difference between chloride and bromide. The group is also working to establish a possible new standard for bromide detection in diagnosis of the disease.

Yang is collaborating with Penn State electrical engineer professor Zhiwen Liu to build a handheld device that can measure salt concentrations in sweat using his citrate-based molecules and a cell phone. This could be especially useful in developing countries where people have limited access to expensive analytical equipment.

‘We are developing a platform material for sensing that is low cost, can be automated, requires no titration by trained staff or expensive instrumentation as in hospitals, and provides fast, almost instantaneous, results,’ said Liu.

‘Beyond cystic fibrosis, our platform can also be used for many other diseases, such as metabolic alkalosis, Addison’s disease, and amyotrophic lateral sclerosis. All of those diseases display abnormal concentrations of chloride in the urine, serum or cerebral spinal fluid,’ Yang said.

According to the U.S. National Library of Medicine, cystic fibrosis is a common genetic disease within the white population in the United States. The disease occurs in 1 in 2,500 to 3,500 white newborns. Cystic fibrosis is less common in other ethnic groups, affecting about 1 in 17,000 African Americans and 1 in 31,000 Asian Americans.’

Penn State news.psu.edu/story/426864/2016/09/20/research/low-cost-sensor-cystic-fibrosis-diagnosis-based-citrate